Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
Org Biomol Chem. 2019 Jan 31;17(5):1176-1190. doi: 10.1039/c8ob02811g.
The influence of chirality on the therapeutic activities of drug molecules has remained an interesting subject matter in drug design. The recent identification of two chiral irreversible inhibitors with differential inhibitory activities towards oncogenic fibroblast growth factor receptor 4 (FGFR4) presented an avenue to investigate the underlying mechanisms that accounted for their disparate activities. Accordingly, the S-configured form (9g) exhibited '15 times' potency than the corresponding R-configured (9h) form. Nonetheless, the big question remains how does chirality influence their inhibitory potencies? Therefore, in this study, we seek to provide useful insights into this interesting phenomenon using molecular dynamics simulations and free binding energy calculations. Interestingly, we observed that the inhibitory 9g activity correlates with a coordinated movement of the active site p-loop, as specifically induced by the S-configuration, which allowed the rotation of three dihedral angles; φ1(CNCO), φ2(CCC*N) and φ3(CCCC), thereby achieving optimal orientations suitable for interactions with crucial active site residues such as LEU473, LYS503, ASP641 and TYR643. Consequentially, while the 9h-bound FGFR4 active site was highly unstable, 9g exerted an inward pulling effect which accounted for active site stability and compactness. Also, the positional movement of 9h (R-configuration) at the active site was restricted, thereby preventing interactions with key residues. Moreover, 9g exhibited the most favorable binding as compared to 9h which showed a relatively lower ΔGbind. The higher binding affinity of 9g to FGFR4 can be mainly attributed to the increase in van der Waals energy by -4.12 kcal mol-1 and electrostatic by -2.89 kcal mol-1. The difference in van der Waals interactions is mainly determined by two residues; ASP641 and TYR643, whilst, the difference in electrostatic interactions is primarily determined by two residues LEU473 and LYS503.
手性对药物分子治疗活性的影响一直是药物设计中一个有趣的课题。最近发现两种手性不可逆抑制剂对致癌性成纤维细胞生长因子受体 4（FGFR4）具有不同的抑制活性，为研究导致它们活性差异的潜在机制提供了途径。相应地，S 构型（9g）的活性比相应的 R 构型（9h）强 15 倍。尽管如此，最大的问题仍然是手性如何影响它们的抑制效力？因此，在这项研究中，我们试图使用分子动力学模拟和自由结合能计算为这一有趣的现象提供有用的见解。有趣的是，我们观察到抑制性 9g 活性与活性部位 p 环的协调运动相关，具体来说，这种运动是由 S 构型诱导的，它允许三个二面角；φ1（CNCO）、φ2（CCC*N）和φ3（CCCC）旋转，从而实现与关键活性部位残基（如 LEU473、LYS503、ASP641 和 TYR643）相互作用的最佳取向。因此，虽然 9h 结合的 FGFR4 活性部位极不稳定，但 9g 产生了向内的拉力，这解释了活性部位的稳定性和紧凑性。此外，9h（R 构型）在活性部位的位置移动受到限制，从而阻止了与关键残基的相互作用。此外，9g 的结合比 9h 更有利，9g 的ΔGbind 相对较低。9g 与 FGFR4 的更高结合亲和力主要归因于范德华能增加了-4.12 kcal mol-1，静电能增加了-2.89 kcal mol-1。范德华相互作用的差异主要由两个残基决定；ASP641 和 TYR643，而静电相互作用的差异主要由两个残基决定；LEU473 和 LYS503。
